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Pragasam AK, Maurya S, Jain K, Pal S, Raja C, Yadav R, Kumar S, Purohit A, Pradhan D, Kajal K, Talukdar D, Singh AN, Verma J, Jana P, Rawat S, Kshetrapal P, Krishna A, Kumar S, Bansal VK, Das B, Srikanth CV, Garg PK. Invasive Salmonella Typhimurium colonizes gallbladder and contributes to gallbladder carcinogenesis through activation of host epigenetic modulator KDM6B. Cancer Lett 2025; 618:217621. [PMID: 40074067 DOI: 10.1016/j.canlet.2025.217621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 02/28/2025] [Accepted: 03/08/2025] [Indexed: 03/14/2025]
Abstract
Gallbladder stones alone do not explain the risk of gallbladder cancer (GBC) as the sole etiological factor. Chronic microbial infection, particularly Salmonella, has been implicated in GB carcinogenesis, but its causative role and the underlying mechanisms are largely unknown. We studied gut and gallbladder tissue microbiome through targeted metagenomics to identify pathogenic bacteria in GBC. Virulence and pathogenicity of identified Salmonella Typhimurium from GBC tissue were studied after culture by whole genome sequencing, phylogenetic analysis, mutational profiling, and pangenome analysis. Mechanistic studies for GBC carcinogenesis were carried out in a mouse model of gallstones and chronic Salmonella infection, a cellular model using GBC (NOZ) cell lines, and a xenograft tumor model. We found an increased abundance of Salmonella in the gut microbiome of patients with GBC and culturable S. Typhimurium from the gallbladder cancer tissue. Comparative genomics of S. Typhimurium isolated from the GBC tissue showed a high invasive index. S. Typhimurium isolates harbored horizontally acquired virulence functions in their accessory genome. Chronic S. Typhimurium infection caused chronic inflammation, pre-malignant changes, and tumor-promoting mechanisms in the mouse model with gallbladder stones with activation of the epigenetic modulator KDM6B both in the mouse model and human GBC. Inhibition of KDM6B reduced engrafted tumor size in SCID mice. Of the differentially regulated genes in human GBC tissue, ADAMTSL5, CX3CR1, and SPSB4 were also significantly dysregulated in NOZ cells infected with Salmonella. Chronic Salmonella infection contributes to gallbladder carcinogenesis through a host epigenetic mechanism involving KDM6B.
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Affiliation(s)
- Agila Kumari Pragasam
- Functional Genomics Laboratory, Centre for Microbial Research, BRIC-Translational Health Science and Technology Institute, Faridabad, 121001, India
| | - Sonalika Maurya
- Laboratory of Gut Infection and Inflammation Biology, Regional Centre for Biotechnology, Faridabad, 121001, India
| | - Kajal Jain
- Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Sujoy Pal
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Christu Raja
- Centralized Core Research Facility, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Rajni Yadav
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Shakti Kumar
- Functional Genomics Laboratory, Centre for Microbial Research, BRIC-Translational Health Science and Technology Institute, Faridabad, 121001, India
| | - Ayushi Purohit
- Functional Genomics Laboratory, Centre for Microbial Research, BRIC-Translational Health Science and Technology Institute, Faridabad, 121001, India
| | - Dibyabhaba Pradhan
- Centralized Core Research Facility, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Kirti Kajal
- Laboratory of Gut Infection and Inflammation Biology, Regional Centre for Biotechnology, Faridabad, 121001, India
| | - Daizee Talukdar
- Functional Genomics Laboratory, Centre for Microbial Research, BRIC-Translational Health Science and Technology Institute, Faridabad, 121001, India
| | - Anand Narayan Singh
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Jyoti Verma
- Functional Genomics Laboratory, Centre for Microbial Research, BRIC-Translational Health Science and Technology Institute, Faridabad, 121001, India
| | - Pradipta Jana
- Functional Genomics Laboratory, Centre for Microbial Research, BRIC-Translational Health Science and Technology Institute, Faridabad, 121001, India
| | - Shefali Rawat
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Pallavi Kshetrapal
- Pediatric Biology Center, BRIC-Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Asuri Krishna
- Centralized Core Research Facility, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Subodh Kumar
- Department of Surgery, JPN Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Virinder Kumar Bansal
- Centralized Core Research Facility, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Bhabatosh Das
- Functional Genomics Laboratory, Centre for Microbial Research, BRIC-Translational Health Science and Technology Institute, Faridabad, 121001, India.
| | - Chittur V Srikanth
- Laboratory of Gut Infection and Inflammation Biology, Regional Centre for Biotechnology, Faridabad, 121001, India.
| | - Pramod Kumar Garg
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, 110029, India.
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Akinsanya A, González IA. Evaluating Intestinal Metaplasia in Pediatric Gallbladder Specimens: Clinicopathologic Significance and Sampling Thresholds. Pediatr Dev Pathol 2025:10935266251341508. [PMID: 40391422 DOI: 10.1177/10935266251341508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/21/2025]
Abstract
BACKGROUND Gallbladders are a commonly encounter specimen in pediatric pathology practice. In the adult population, intestinal metaplasia (IM) in the gallbladder is associated with the development of dysplasia and adenocarcinoma; however, in children its significance is unknown, and the appropriate sampling has not been described which is the goal of this study. METHODS Twenty-five routine pediatric cholecystectomy cases with IM were identified, and their clinical and histologic findings were reviewed. RESULTS Of these 25 cases, 23 were female (92%). The most common indication for surgery was cholelithiasis (84%). Stones were present in 21 cases (84%). Twenty-three cases (92%) had additional sections submitted with an average of 3.9 slides (range = 3-6), and 52% had IM in additional blocks. However, no dysplasia or carcinoma was identified in any case. CONCLUSION IM in the gallbladder is frequently seen in the setting of gallstones and chronic inflammation. Based on our experience, no additional sampling is required when incidentally identified.
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Affiliation(s)
- Adeyinka Akinsanya
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Iván A González
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
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Baruah C, Jorvekar SB, Sarma A, Gogoi G, Roy N, Dutta U, Khanna S, Borkar RM, Kumar A, Barah P. Gallstone Physicochemical Properties and Heavy Metal Concentrations Associated with Gallbladder Carcinogenesis in Assam, India. Chem Res Toxicol 2025; 38:598-608. [PMID: 40172547 DOI: 10.1021/acs.chemrestox.4c00392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2025]
Abstract
Gallbladder cancer (GBC) is an aggressive malignancy, with gallstone disease (GSD) recognized as the primary risk factor. Although the precise mechanism linking GSD to GBC remains unclear, evidence suggests that gallstone characteristics play a significant role. This study investigates the physicochemical characteristics of gallstones critical for GBC development. We analyzed 40 gallstone samples from 30 GSD and 10 GBC with GSD (GBCGS) patients using advanced spectroscopic and imaging techniques such as fourier transform infrared (FTIR), powder X-ray diffraction (PXRD), nuclear magnetic resonance (NMR), and scanning electron microscopy energy-dispersive X-ray (SEM-EDX)). Subsequently, elemental analysis of 10 gallstones each from GBCGS and GSD was conducted via inductively coupled plasma-mass spectrometry (ICP-MS). Gallstones from the GSD group were identified as cholesterol (70%), mixed (13.3%), pigment (6.7%), and calcium carbonate (10%), while the GBCGS group included only cholesterol (70%) and mixed (30%) types. Cholesterol was the dominant organic component in most gallstones, with the cholesterol and mixed types exhibiting highly crystalline phases characterized by a stacked plate-like microstructure, particularly prominent in the GBCGS group. Additionally, the GBCGS group revealed significantly higher concentrations of carcinogenic elements such as arsenic, chromium, mercury, iron, and lead (p < 0.05), suggesting their accumulation in the gallbladder and gallstones. Consequently, our findings highlight that the physicochemical properties of cholesterol-rich gallstones and exposure to carcinogenic elements play a key role in the pathogenesis of GBC in Assam. These results emphasize the need for further research into cholesterol dysregulation and its link to elemental toxicity.
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Affiliation(s)
- Cinmoyee Baruah
- Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, Assam 784028, India
| | - Sachin B Jorvekar
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Guwahati, Assam 781101, India
| | - Anupam Sarma
- Department of Onco-pathology, Dr. Bhubaneswar Borooah Cancer Institute, Guwahati, Assam 781016, India
| | - Gayatri Gogoi
- Department of Pathology, Assam Medical College and Hospital, Dibrugarh, Assam 786002, India
| | - Nabanita Roy
- Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, Assam 784028, India
| | - Utpal Dutta
- Department of Pathology, Assam Medical College and Hospital, Dibrugarh, Assam 786002, India
| | - Subhash Khanna
- Department of Minimal Access, Gastro Intestinal, Bariatric and Robotic Surgery, Swagat Super Speciality, and Surgical Hospital, Guwahati 781011, India
| | - Roshan M Borkar
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Guwahati, Assam 781101, India
| | - Akshai Kumar
- Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
- Jyoti and Bhupat Mehta School of Health Science and Technology, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
- Centre for Nanotechnology, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Pankaj Barah
- Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, Assam 784028, India
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Bojan A, Pricop C, Vladeanu MC, Bararu-Bojan I, Halitchi CO, Giusca SE, Badulescu OV, Ciocoiu M, Iliescu-Halitchi D, Foia LG. The Predictive Roles of Tumour Markers, Hemostasis Assessment, and Inflammation in the Early Detection and Prognosis of Gallbladder Adenocarcinoma and Metaplasia: A Clinical Study. Int J Mol Sci 2025; 26:3665. [PMID: 40332145 PMCID: PMC12027584 DOI: 10.3390/ijms26083665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/03/2025] [Accepted: 04/10/2025] [Indexed: 05/08/2025] Open
Abstract
Gallbladder carcinoma (GBC) is one of the most aggressive malignancies of the biliary tract, often originating from chronic inflammation associated with gallstones and cholecystitis. Persistent inflammation plays a pivotal role in the development of preneoplastic changes, such as metaplasia, which may progress to malignancy. Despite its relatively low incidence, GBC is characterized by a poor prognosis due to late-stage diagnosis, highlighting the urgent need for improved early detection strategies. This study aimed to assess the diagnostic and prognostic significance of CA 19-9 and CEA levels in patients with gallbladder lesions, while also evaluating systemic inflammation and hemostatic dysregulation. A retrospective analysis was conducted on patients diagnosed with gallbladder lesions, with histopathological confirmation of adenocarcinoma and metaplasia. Laboratory assessments included serum levels of tumour markers, inflammatory markers such as CRP, and key hemostatic parameters, including thrombocyte count, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen levels. A predictive scoring model was developed using the cutoff values of CA 19-9 and CEA to assess their combined diagnostic potential. Among the patients studied, 48.9% had an initial diagnosis of chronic cholecystitis, while 32.2% presented with acute cholecystitis. Adenocarcinoma was identified in 6.7% of cases after histopathological examination, predominantly in females over 65 years old with acute cholecystitis. Metaplasia was detected in 7.8% of cases, primarily in elderly females with chronic cholecystitis. Laboratory findings revealed significantly elevated levels of CA 19-9, CEA, AFP, and CA-125 in patients with adenocarcinoma. Additionally, abnormalities in hemostatic parameters, including increased fibrinogen levels and alterations in thrombocyte count, were observed in patients with malignancy. A combined predictive score using CA 19-9 and CEA demonstrated strong potential for detecting adenocarcinoma and metaplasia, improving diagnostic accuracy. Our findings emphasize the clinical importance of integrating tumour markers, inflammatory biomarkers, and hemostatic parameters in the evaluation of gallbladder lesions associated with chronic inflammation. The combined assessment of these factors enhances early detection, facilitates malignancy risk stratification, and improves prognostic evaluation, particularly in patients with metabolic and cardiovascular comorbidities.
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Affiliation(s)
- Andrei Bojan
- Department of Surgical Specialties I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700111 Iasi, Romania; (A.B.)
| | - Catalin Pricop
- Department of Surgical Specialties I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700111 Iasi, Romania; (A.B.)
| | - Maria-Cristina Vladeanu
- Department of Morpho Functional Sciences, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700111 Iasi, Romania (M.C.)
| | - Iris Bararu-Bojan
- Department of Morpho Functional Sciences, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700111 Iasi, Romania (M.C.)
| | - Codruta Olimpiada Halitchi
- Department of Pediatry, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700111 Iasi, Romania
| | - Simona Eliza Giusca
- Department of Morpho Functional Sciences, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700111 Iasi, Romania (M.C.)
| | - Oana Viola Badulescu
- Department of Morpho Functional Sciences, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700111 Iasi, Romania (M.C.)
| | - Manuela Ciocoiu
- Department of Morpho Functional Sciences, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700111 Iasi, Romania (M.C.)
| | - Dan Iliescu-Halitchi
- Department of Medical Sciences, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700111 Iasi, Romania
| | - Liliana Georgeta Foia
- Discipline of Biochemistry, Faculty of Dental Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
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Zanchetta M, Adani GL, Micheletti G, Poto GE, Piccioni SA, Carbone L, Monteleone I, Sandini M, Marrelli D, Calomino N. Perforated Calculous Cholecystitis and Incidental Squamous Cell Carcinoma of the Gallbladder-A Complex Relationship with a Difficult Management in the Acute Setting. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:452. [PMID: 40142263 PMCID: PMC11944027 DOI: 10.3390/medicina61030452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 02/23/2025] [Accepted: 03/04/2025] [Indexed: 03/28/2025]
Abstract
The worldwide prevalence of gallstones (GSs) is estimated to be between 10% and 15% in the general population. Gallbladder carcinoma (GBC) is the most common biliary tract neoplasia, and it is characterized by highly aggressive behavior and poor overall prognosis. Long-standing GSs and chronic inflammatory state represent the most common risk factors for GBC, promoting a carcinogenic microenvironment. Long-standing GSs expose patients to potentially severe surgical and oncological complications. A 71-year-old gentleman, who had never experienced biliary symptoms and had diabetes mellitus (DM), presented with severe peritonitis due to perforated acute calculous cholecystitis. The patient underwent an emergent laparotomic cholecystectomy. Histopathology found a rare pT2b poorly differentiated squamocellular carcinoma of the gallbladder. Although more difficult due to the concomitant inflammatory context, it is critical to identify suspicious lesions during preoperative imaging in patients at high risk of malignancy presenting with complex acute gallbladder pathologies. A review of the literature was conducted to gain a deeper insight into the relationship between long-standing GSs and GBC, evaluating also the difficult diagnosis and management of malignancy in the acute setting. Considering the existing literature, the choice to pursue a prophylactic cholecystectomy may be justifiable in selected asymptomatic GS patients at high risk for GBC.
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Affiliation(s)
- Matteo Zanchetta
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Gian Luigi Adani
- Kidney Transplant Unit, Department of Medicine, Surgery and Neuroscience, Siena University Hospital, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Giorgio Micheletti
- Kidney Transplant Unit, Department of Medicine, Surgery and Neuroscience, Siena University Hospital, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Gianmario Edoardo Poto
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Stefania Angela Piccioni
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Ludovico Carbone
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Ilaria Monteleone
- Diagnostic Imaging Unit, Department of Medical, Surgical and Neurosciences, Siena University Hospital, Azienda Ospedaliera Universitaria Senese, Viale Bracci 10, 53100 Siena, Italy
| | - Marta Sandini
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Daniele Marrelli
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Natale Calomino
- Kidney Transplant Unit, Department of Medicine, Surgery and Neuroscience, Siena University Hospital, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
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Mondaca S, Walch H, Sepúlveda S, Schultz N, Muñoz G, Yaqubie A, Macanas P, Pareja C, Garcia P, Chatila W, Nervi B, Li B, Harding JJ, Viviani P, Roa JC, Abou-Alfa GK. Clinical and Genomic Characterization of ERBB2-Altered Gallbladder Cancer: Exploring Differences Between an American and a Chilean Cohort. JCO Glob Oncol 2024; 10:e2400090. [PMID: 39388662 PMCID: PMC11487998 DOI: 10.1200/go.24.00090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 06/03/2024] [Accepted: 08/02/2024] [Indexed: 10/12/2024] Open
Abstract
PURPOSE Gallbladder cancer (GBC) is a biliary tract malignancy characterized by its high lethality. Although the incidence of GBC is low in most countries, specific areas such as Chile display a high incidence. Our collaborative study sought to compare clinical and molecular features of GBC cohorts from Chile and the United States with a focus on ERBB2 alterations. METHODS Patients were accrued at Memorial Sloan Kettering Cancer Center (MSK) or the Pontificia Universidad Católica de Chile (PUC). Clinical information was retrieved from medical records. Genomic analysis was performed by the next-generation sequencing platform MSK-Integrated Mutation Profiling of Actionable Cancer Targets. RESULTS A total of 260 patients with GBC were included, 237 from MSK and 23 from PUC. There were no significant differences in the clinical characteristics between the patients identified at MSK and at PUC except in terms of lithiasis prevalence which was significantly higher in the PUC cohort (85% v 44%; P = .0003). The prevalence of ERBB2 alterations was comparable between the two cohorts (15% v 9%; P = .42). Overall, ERBB2 alterations were present in 14% of patients (8% with ERBB2 amplification, 4% ERBB2 mutation, 1.5% concurrent amplification and mutation, and 0.4% ERBB2 fusion). Notably, patients with GBC that harbored ERBB2 alterations had better overall survival (OS) versus their ERBB2-wild type counterparts (22.3 months v 11.8 months; P = .024). CONCLUSION The prevalence of lithiasis seems to be higher in Chilean versus US patients with GBC. A similar prevalence of ERBB2 alterations of overall 14% and better OS suggests that a proportion of them could benefit from human epidermal growth factor receptor type 2-targeted therapies. The smaller cohort of Chile, where the disease prevalence is higher, is a reminder and invitation for the need of more robust next-generation sequencing analyses globally.
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Affiliation(s)
- Sebastián Mondaca
- Department of Hematology and Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Henry Walch
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Santiago Sepúlveda
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Nikolaus Schultz
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Gonzalo Muñoz
- Department of Hematology and Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Amin Yaqubie
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Patricia Macanas
- Department of Hematology and Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Center for Cancer Prevention and Control, CECAN, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Claudia Pareja
- Department of Hematology and Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Patricia Garcia
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Center for Cancer Prevention and Control, CECAN, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Walid Chatila
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Bruno Nervi
- Department of Hematology and Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Center for Cancer Prevention and Control, CECAN, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Bob Li
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Medical College at Cornell University, Cancer Center, New York, NY
| | - James J. Harding
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Medical College at Cornell University, Cancer Center, New York, NY
| | - Paola Viviani
- Department of Public Health, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Carlos Roa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Center for Cancer Prevention and Control, CECAN, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ghassan K. Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Medical College at Cornell University, Cancer Center, New York, NY
- Trinity College, Dublin Medical School, Dublin, Ireland
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Kumar A, Sarangi Y, Gupta A, Sharma A. Gallbladder cancer: Progress in the Indian subcontinent. World J Clin Oncol 2024; 15:695-716. [PMID: 38946839 PMCID: PMC11212610 DOI: 10.5306/wjco.v15.i6.695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/25/2024] [Accepted: 05/15/2024] [Indexed: 06/24/2024] Open
Abstract
Gallbladder cancer (GBC) is one of the commonest biliary malignancies seen in India, Argentina, and Japan. The disease has dismal outcome as it is detected quite late due to nonspecific symptoms and signs. Early detection is the only way to improve the outcome. There have been several advances in basic as well as clinical research in the hepatobiliary and pancreatic diseases in the West and other developed countries but not enough has been done in GBC. Therefore, it is important and the responsibility of the countries with high burden of GBC to find solutions to the many unanswered questions like etiopathogenesis, early diagnosis, treatment, and prognostication. As India being one of the largest hubs for GBC in the world, it is important to know how the country has progressed on GBC. In this review, we will discuss the outcome of the publications from India highlighting the work and the developments taken place in past several decades both in basic and clinical research.
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Affiliation(s)
- Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Yajnadatta Sarangi
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Annapurna Gupta
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Aarti Sharma
- Division of Haematology, Mayo Clinic Arizona, Phoenix, AZ 85054, United States
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Bojan A, Pricop C, Ciocoiu M, Vladeanu MC, Bararu Bojan I, Badulescu OV, Badescu MC, Plesoianu CE, Halitchi DI, Foia LG. Environmental and Metabolic Risk Factors Linked to Gallbladder Dysplasia. Metabolites 2024; 14:273. [PMID: 38786750 PMCID: PMC11123122 DOI: 10.3390/metabo14050273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 04/25/2024] [Accepted: 04/28/2024] [Indexed: 05/25/2024] Open
Abstract
Gallbladder disorders encompass a spectrum from congenital anomalies to inflammatory and neoplastic conditions, frequently requiring surgical intervention. Epithelial abnormalities like adenoma and metaplasia have the potential to progress to carcinoma, emphasizing the importance of histopathological assessment for early detection of malignancy. Gallbladder cancer (GBC) may be incidentally discovered during cholecystectomy for presumed benign conditions, underscoring the need for a thorough examination. However, the lack of clarity regarding the molecular mechanisms of GBC has impeded diagnostic and therapeutic advancements. Timely detection is crucial due to GBC's aggressive nature and poor prognosis. Chronic inflammation plays a central role in carcinogenesis, causing DNA damage and oncogenic alterations due to persistent insults. Inflammatory cytokines and microRNAs are among the various mediators contributing to this process. Gallbladder calcifications, particularly stippled ones, may signal malignancy and warrant preemptive removal. Molecular pathways involving mutations in oncogenes and tumor suppressor genes drive GBC pathogenesis, with proposed sequences such as gallstone-induced inflammation leading to carcinoma formation. Understanding these mechanisms, alongside evaluating mucin characteristics and gene mutations, can deepen comprehension of GBC's pathophysiology. This, in turn, facilitates the identification of high-risk individuals and the development of improved treatment strategies, ultimately enhancing patient outcomes. Thus, in this review, our aim has been to underscore the primary mechanisms underlying the development of gallbladder dysplasia and neoplasia.
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Affiliation(s)
- Andrei Bojan
- Department of Surgical Sciences, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania (C.P.)
| | - Catalin Pricop
- Department of Surgical Sciences, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania (C.P.)
| | - Manuela Ciocoiu
- Department of Pathophysiology, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania; (M.C.V.)
| | - Maria Cristina Vladeanu
- Department of Pathophysiology, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania; (M.C.V.)
| | - Iris Bararu Bojan
- Department of Pathophysiology, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania; (M.C.V.)
| | - Oana Viola Badulescu
- Department of Pathophysiology, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania; (M.C.V.)
| | - Minerva Codruta Badescu
- Department of Internal Medicine, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania; (M.C.B.)
| | - Carmen Elena Plesoianu
- Department of Internal Medicine, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania; (M.C.B.)
| | - Dan Iliescu Halitchi
- Department of Internal Medicine, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania; (M.C.B.)
| | - Liliana Georgeta Foia
- Department of Biochemistry, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania;
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9
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Manzano-Núñez F, Prates Tiago Aguilar L, Sempoux C, Lemaigre FP. Biliary Tract Cancer: Molecular Biology of Precursor Lesions. Semin Liver Dis 2023; 43:472-484. [PMID: 37944999 DOI: 10.1055/a-2207-9834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2023]
Abstract
Biliary tract cancer is a devastating malignancy of the bile ducts and gallbladder with a dismal prognosis. The study of precancerous lesions has received considerable attention and led to a histopathological classification which, in some respects, remains an evolving field. Consequently, increasing efforts have been devoted to characterizing the molecular pathogenesis of the precursor lesions, with the aim of better understanding the mechanisms of tumor progression, and with the ultimate goal of meeting the challenges of early diagnosis and treatment. This review delves into the molecular mechanisms that initiate and promote the development of precursor lesions of intra- and extrahepatic cholangiocarcinoma and of gallbladder carcinoma. It addresses the genomic, epigenomic, and transcriptomic landscape of these precursors and provides an overview of animal and organoid models used to study them. In conclusion, this review summarizes the known molecular features of precancerous lesions in biliary tract cancer and highlights our fragmentary knowledge of the molecular pathogenesis of tumor initiation.
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Affiliation(s)
| | | | - Christine Sempoux
- Institute of Pathology, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland
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10
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Abstract
In recent times Gallbladder cancer (GBC) incidences increased many folds in India and are being reported from arsenic hotspots identified in Bihar. The study aims to establish association between arsenic exposure and gallbladder carcinogenesis. In the present study, n = 200 were control volunteers and n = 152 confirmed gallbladder cancer cases. The studied GBC patient's biological samples-gallbladder tissue, gallbladder stone, bile, blood and hair samples were collected for arsenic estimation. Moreover, n = 512 gallbladder cancer patients blood samples were also evaluated for the presence of arsenic to understand exposure level in the population. A significantly high arsenic concentration (p < 0.05) was detected in the blood samples with maximum concentration 389 µg/L in GBC cases in comparison to control. Similarly, in the gallbladder cancer patients, there was significantly high arsenic concentration observed in gallbladder tissue with highest concentration of 2166 µg/kg, in gallbladder stones 635 µg/kg, in bile samples 483 µg/L and in hair samples 6980 µg/kg respectively. Moreover, the n = 512 gallbladder cancer patient's blood samples study revealed very significant arsenic concentration in the population of Bihar with maximum arsenic concentration as 746 µg/L. The raised arsenic concentration in the gallbladder cancer patients' biological samples-gallbladder tissue, gallbladder stone, bile, blood, and hair samples was significantly very high in the arsenic exposed area. The study denotes that the gallbladder disease burden is very high in the arsenic exposed area of Bihar. The findings do provide a strong link between arsenic contamination and increased gallbladder carcinogenesis.
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11
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Yang S, Qin L, Wu P, Liu Y, Zhang Y, Mao B, Yan Y, Yan S, Tan F, Yue X, Liu H, Xue H. RNA sequencing revealed the multi-stage transcriptome transformations during the development of gallbladder cancer associated with chronic inflammation. PLoS One 2023; 18:e0283770. [PMID: 36996251 PMCID: PMC10062614 DOI: 10.1371/journal.pone.0283770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 03/15/2023] [Indexed: 04/01/2023] Open
Abstract
Gallbladder cancer (GBC) is a highly malignant tumor with extremely poor prognosis. Previous studies have suggested that the carcinogenesis and progression of GBC is a multi-stage and multi-step process, but most of them focused on the genome changes. And a few studies just compared the transcriptome differences between tumor tissues and adjacent noncancerous tissues. The transcriptome changes, relating to every stage of GBC evolution, have rarely been studied. We selected three cases of normal gallbladder, four cases of gallbladder with chronic inflammation induced by gallstones, five cases of early GBC, and five cases of advanced GBC, using next-generation RNA sequencing to reveal the changes in mRNAs and lncRNAs expression during the evolution of GBC. In-depth analysis of the sequencing data indicated that transcriptome changes from normal gallbladder to gallbladder with chronic inflammation were distinctly related to inflammation, lipid metabolism, and sex hormone metabolism; transcriptome changes from gallbladder with chronic inflammation to early GBC were distinctly related to immune activities and connection between cells; and the transcriptome changes from early GBC to advanced GBC were distinctly related to transmembrane transport of substances and migration of cells. Expression profiles of mRNAs and lncRNAs change significantly during the evolution of GBC, in which lipid-based metabolic abnormalities play an important promotive role, inflammation and immune activities play a key role, and membrane proteins are very highlighted molecular changes.
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Affiliation(s)
- Sen Yang
- Department of Hepatobiliary and Pancreatic Surgery, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Litao Qin
- Medical Genetic Institute of Henan Province, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Pan Wu
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People's Hospital, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Yanbing Liu
- Department of Hepatobiliary and Pancreatic Surgery, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Yanling Zhang
- Department of Pathology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Bing Mao
- Department of Clinical Research Service Center, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Yiyang Yan
- Department of Hepatobiliary and Pancreatic Surgery, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Shuai Yan
- Department of Hepatobiliary and Pancreatic Surgery, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Feilong Tan
- Department of Hepatobiliary and Pancreatic Surgery, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Xueliang Yue
- Department of Hepatobiliary and Pancreatic Surgery, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Hongshan Liu
- Department of Hepatobiliary and Pancreatic Surgery, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Huanzhou Xue
- Department of Hepatobiliary and Pancreatic Surgery, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
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12
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Zhu Z, Luo K, Zhang B, Wang G, Guo K, Huang P, Liu Q. Risk factor analysis and construction of prediction models of gallbladder carcinoma in patients with gallstones. Front Oncol 2023; 13:1037194. [PMID: 36923422 PMCID: PMC10009222 DOI: 10.3389/fonc.2023.1037194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 02/13/2023] [Indexed: 03/03/2023] Open
Abstract
Background Gallbladder carcinoma (GBC) is a biliary tract tumor with a high mortality rate. The objectives of this study were to explore the risk factors of GBC in patients with gallstones and to establish effective screening indicators. Methods A total of 588 patients from medical centers in two different regions of China were included in this study and defined as the internal test samples and the external validation samples, respectively. We retrospectively reviewed the differences in clinicopathologic data of the internal test samples to find the independent risk factors that affect the occurrence of GBC. Then, we constructed three different combined predictive factors (CPFs) through the weighting method, integral system, and nomogram, respectively, and named them CPF-A, CPF-B, and CPF-C sequentially. Furthermore, we evaluated these indicators through calibration and DCA curves. The ROC curve was used to analyze their diagnostic efficiency. Finally, their diagnostic capabilities were validated in the external validation samples. Results In the internal test samples, the results showed that five factors, namely, age (RR = 3.077, 95% CI: 1.731-5.496), size of gallstones (RR = 13.732, 95% CI: 5.937-31.762), course of gallstones (RR = 2.438, 95% CI: 1.350-4.403), CEA (RR = 9.464, 95% CI: 3.394-26.392), and CA199 (RR = 9.605, 95% CI: 4.512-20.446), were independent risk factors for GBC in patients with gallstones. Then, we established three predictive indicators: CPF-A, CPF-B, and CPF-C. These models were further validated using bootstrapping with 1,000 repetitions. Calibration and decision curve analysis showed that the three models fit well. Meanwhile, multivariate analysis showed that CPF-B and CPF-C were independent risk factors for GBC in patients with gallstones. In addition, the validation results of the external validation samples are essentially consistent with the internal test samples. Conclusion Age (≤58.5 vs. >58.5 years), size of gallstones (≤1.95 vs. >1.95cm), course of gallstones (≤10 vs. >10 years), CEA (≤5 vs. >5 ng/ml), and CA199 (≤37 vs. >37 U/ml) are independent risk factors for GBC in patients with gallstones. When positive indicators were ≥2 among the five independent risk factors or the score of the nomogram was >82.64, the risk of GBC was high in gallstone patients.
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Affiliation(s)
- Zhencheng Zhu
- Department of Hepatobiliary Surgery, Zhangjiagang City First People's Hospital, Suzhou, China
| | - Kunlun Luo
- Department of Hepatobiliary Surgery, The 904th Hospital of Joint Logistic Support Force of PLA, Wuxi, China
| | - Bo Zhang
- Department of Hepatobiliary Surgery, Zhangjiagang City First People's Hospital, Suzhou, China
| | - Gang Wang
- Department of Hepatobiliary Surgery, Zhangjiagang City First People's Hospital, Suzhou, China
| | - Ke Guo
- Department of Hepatobiliary Surgery, Zhangjiagang City First People's Hospital, Suzhou, China
| | - Pin Huang
- Department of Hepatobiliary Surgery, Zhangjiagang City First People's Hospital, Suzhou, China
| | - Qiuhua Liu
- Department of Hepatobiliary Surgery, Zhangjiagang City First People's Hospital, Suzhou, China
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13
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Abstract
Gallbladder cancer (GBC) is the most common cancer of the biliary tract, characterized by a very poor prognosis when diagnosed at advanced stages owing to its aggressive behaviour and limited therapeutic options. Early detection at a curable stage remains challenging because patients rarely exhibit symptoms; indeed, most GBCs are discovered incidentally following cholecystectomy for symptomatic gallbladder stones. Long-standing chronic inflammation is an important driver of GBC, regardless of the lithiasic or non-lithiasic origin. Advances in omics technologies have provided a deeper understanding of GBC pathogenesis, uncovering mechanisms associated with inflammation-driven tumour initiation and progression. Surgical resection is the only treatment with curative intent for GBC but very few cases are suitable for resection and most adjuvant therapy has a very low response rate. Several unmet clinical needs require to be addressed to improve GBC management, including discovery and validation of reliable biomarkers for screening, therapy selection and prognosis. Standardization of preneoplastic and neoplastic lesion nomenclature, as well as surgical specimen processing and sampling, now provides reproducible and comparable research data that provide a basis for identifying and implementing early detection strategies and improving drug discovery. Advances in the understanding of next-generation sequencing, multidisciplinary care for GBC, neoadjuvant and adjuvant strategies, and novel systemic therapies including chemotherapy and immunotherapies are gradually changing the treatment paradigm and prognosis of this recalcitrant cancer.
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Affiliation(s)
- Juan C Roa
- Department of Pathology, Millennium Institute on Immunology and Immunotherapy, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
| | - Patricia García
- Department of Pathology, Millennium Institute on Immunology and Immunotherapy, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Vinay K Kapoor
- Department of Hepato-pancreato-biliary (HPB) Surgery, Mahatma Gandhi Medical College & Hospital (MGMCH), Jaipur, India
| | - Shishir K Maithel
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Milind Javle
- Department of Gastrointestinal Medical Oncology, UT M.D. Anderson Cancer Center, Houston, TX, USA
| | - Jill Koshiol
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
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14
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Environmental and Lifestyle Risk Factors in the Carcinogenesis of Gallbladder Cancer. J Pers Med 2022; 12:jpm12020234. [PMID: 35207722 PMCID: PMC8877116 DOI: 10.3390/jpm12020234] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 11/08/2021] [Accepted: 12/23/2021] [Indexed: 02/01/2023] Open
Abstract
Gallbladder cancer (GBC) is an aggressive neoplasm that in an early stage is generally asymptomatic and, in most cases, is diagnosed in advanced stages with a very low life expectancy because there is no curative treatment. Therefore, understanding the early carcinogenic mechanisms of this pathology is crucial to proposing preventive strategies for this cancer. The main risk factor is the presence of gallstones, which are associated with some environmental factors such as a sedentary lifestyle and a high-fat diet. Other risk factors such as autoimmune disorders and bacterial, parasitic and fungal infections have also been described. All these factors can generate a long-term inflammatory state characterized by the persistent activation of the immune system, the frequent release of pro-inflammatory cytokines, and the constant production of reactive oxygen species that result in a chronic damage/repair cycle, subsequently inducing the loss of the normal architecture of the gallbladder mucosa that leads to the development of GBC. This review addresses how the different risk factors could promote a chronic inflammatory state essential to the development of gallbladder carcinogenesis, which will make it possible to define some strategies such as anti-inflammatory drugs or public health proposals in the prevention of GBC.
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15
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Precursor Lesions of Gallbladder Carcinoma: Disease Concept, Pathology, and Genetics. Diagnostics (Basel) 2022; 12:diagnostics12020341. [PMID: 35204432 PMCID: PMC8871096 DOI: 10.3390/diagnostics12020341] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 01/22/2022] [Accepted: 01/27/2022] [Indexed: 02/05/2023] Open
Abstract
Understanding the pathogenesis and carcinogenesis of gallbladder adenocarcinoma is important. The fifth edition of the World Health Organization’s tumor classification of the digestive system indicates three types of preinvasive neoplasm of the gallbladder: pyloric gland adenoma (PGA), biliary intraepithelial neoplasia (BilIN), and intracholecystic papillary neoplasm (ICPN). New terminologies have also been introduced, such as intracholecystic papillary-tubular neoplasm, gastric pyloric, simple mucinous type, and intracholecystic tubular non-mucinous neoplasm (ICTN). Pancreatobiliary maljunction (PBM) poses a markedly high risk for bile duct carcinoma, which was analyzed and investigated mainly by Asian researchers in the past; however, recent studies have clarified a similar significance of biliary carcinogenesis in Western countries as well. In this study, we reviewed and summarized information on three gallbladder neoplastic precursors, PGA, BilIN, and ICPN, and gallbladder lesions in patients with PBM.
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16
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Genomic characterization of co-existing neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer. Nat Commun 2021; 12:4753. [PMID: 34362903 PMCID: PMC8346570 DOI: 10.1038/s41467-021-25012-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 07/16/2021] [Indexed: 12/30/2022] Open
Abstract
Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. However, the genetic and evolutionary relationships between BilIN and carcinoma remain unclear. Here we perform whole-exome sequencing of coexisting low-grade BilIN (adenoma), high-grade BilIN, and carcinoma lesions, and normal tissues from the same patients. We identify aging as a major factor contributing to accumulated mutations and a critical role of CTNNB1 mutations in these tumors. We reveal two distinct carcinoma evolutionary paths: carcinoma can either diverge earlier and evolve more independently or form through the classic adenoma/dysplasia-carcinoma sequence model. Our analysis suggests that extensive loss-of-heterozygosity and mutation events in the initial stage tend to result in a cancerous niche, leading to the subsequent BilIN-independent path. These results reframes our understanding of tumor transformation and the evolutionary trajectory of carcinogenesis in the gallbladder, laying a foundation for the early diagnosis and effective treatment of gallbladder cancer. The progression from biliary tract intraepithelial neoplasia (BilIN) to gallbladder carcinoma (GBC) remains unclear. Here the authors use genomics to analyze coexisting GBC lesions, low-grade and high-grade BilINs, revealing two distinct evolutionary paths for GBC development.
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17
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Srivastava V, Verma K, Puneet. Surgical Management of Gallbladder Carcinoma. Indian J Surg 2021. [DOI: 10.1007/s12262-019-02050-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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18
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Hu C, Wang X, Pan Y, Shu L, Wu F. Occurrence of quadruple squamous cell carcinoma following allogeneic hematopoietic stem cell transplantation for leukemia: A case report. Oncol Lett 2021; 21:341. [PMID: 33747198 DOI: 10.3892/ol.2021.12602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 09/15/2020] [Indexed: 11/06/2022] Open
Abstract
The present case study investigated a rare case of quadruple squamous cell carcinoma following allogeneic hematopoietic stem cell transplantation (HSCT) for leukemia. The main aim of the case study was to determine the pathogenesis and provide novel methods for the diagnosis and treatment of similar cases. The presence of genetic mutations in the p53, EGFR, KRAS and BRAF genes were analyzed and the presence of microsatellite instability (MSI) was determined. In addition, the expression levels of the proteins p53 and EGFR were investigated. The results identified a genetic mutation in p53, of which its expression levels were upregulated. In addition, the majority of the tumor tissues presented with MSI. Therefore, the present findings suggested that the genetic mutations in p53 caused by MSI following allogeneic HSCT may promote tumorigenesis. In addition, the expression levels of the EGFR protein were upregulated, leading to an increase in MAPK signaling pathway activation, which may also serve an important role.
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Affiliation(s)
- Chunhong Hu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Xue Wang
- Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Yue Pan
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Long Shu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Fang Wu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
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19
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Epidemiology of HPB malignancy in the elderly. Eur J Surg Oncol 2021; 47:503-513. [PMID: 32360064 DOI: 10.1016/j.ejso.2020.03.222] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 03/17/2020] [Accepted: 03/26/2020] [Indexed: 02/08/2023] Open
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20
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Montalvo-Jave EE, Rahnemai-Azar AA, Papaconstantinou D, Deloiza ME, Tsilimigras DI, Moris D, Mendoza-Barrera GE, Weber SM, Pawlik TM. Molecular pathways and potential biomarkers in gallbladder cancer: A comprehensive review. Surg Oncol 2019; 31:83-89. [PMID: 31541911 DOI: 10.1016/j.suronc.2019.09.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Accepted: 09/12/2019] [Indexed: 12/13/2022]
Abstract
The most common malignancy of the biliary tract, gallbladder cancer (GBC) often has a dismal prognosis. The aggressive nature of the tumor, delayed diagnosis at advanced stages of the disease, and lack of effective treatment options are some of the factors that contribute to a poor outcome. Early detection and accurate assessment of disease burden is critical to optimize management and improve long-term survival, as well as identify patients for adjuvant therapy and clinical trials. With recent advances in the understanding of the molecular pathogenesis of GBC, several specific diagnostic and biomarkers have been proposed as being of diagnostic and prognostic importance. Indeed, identification of novel diagnostic and prognostic markers has an important role in early diagnosis and development of targeted therapies among patients with GBC. Next-generation sequencing technology and genomewide data analysis have provided novel insight into understanding the molecular pathogenesis of biliary tract cancers, thereby identifying potential biomarkers for clinical use. We herein review available GBC biomarkers and the potential clinical implications in the management of GBC.
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Affiliation(s)
- Eduardo E Montalvo-Jave
- Servicio de Cirugía General, Clínica de Cirugía Hepato-Pancreato-Biliary, Hospital General de México, Mexico; Departamento de Cirugía, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico
| | - Amir A Rahnemai-Azar
- Department of Surgery, Division of Surgical Oncology, Kaiser Permanente School of Medicine, Los Angeles, CA, USA
| | | | - Mariana Espejel Deloiza
- Departamento de Cirugía, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico
| | - Diamantis I Tsilimigras
- Department of Surgery, Division of Surgical Oncology, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Dimitrios Moris
- Department of Surgery, Division of Surgical Oncology, The Ohio State University College of Medicine, Columbus, OH, USA
| | | | - Sharon M Weber
- Department of Surgery, Division of Surgical Oncology, University of Wisconsin Hospital, Madison, WI, USA
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University College of Medicine, Columbus, OH, USA.
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21
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Copy number variants in lipid metabolism genes are associated with gallstones disease in men. Eur J Hum Genet 2019; 28:264-273. [PMID: 31485028 PMCID: PMC6974590 DOI: 10.1038/s41431-019-0501-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 08/02/2019] [Indexed: 11/21/2022] Open
Abstract
Gallstones Disease (GSD) is one of the most common digestive diseases requiring hospitalization and surgical procedures in the world. GSD has a high prevalence in populations with European or Amerindian ancestry (10–20%) and the influence of genetic factors is broadly acknowledged. However, known genetic variants do not entirely explain the disease heritability suggesting that additional genetic variants remain to be identified. Here, we examined the association of copy number variants (CNVs) with GSD in a sample of 4778 individuals (1929 GSD cases and 2849 controls) including two European cohorts from Germany (n = 3702) and one admixed Latin American cohort from Chile (n = 1076). We detected 2936 large and rare CNVs events (size > 100 kb, frequency < 1%). Case-control burden analysis and generalized linear regression models revealed significant association of CNVs with GSD in men, with the strongest effect observed with CNVs overlapping lipid metabolism genes (p-value = 6.54 × 10–4; OR = 2.76; CI 95% = 1.53–4.89). Our results indicate a clear link between CNVs and GSD in men and provides additional evidence that the genetic components of risk for GSD are complex, can be sex specific and include CNVs affecting genes involved in lipid metabolism.
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22
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Abstract
According to GLOBOCAN 2018 data, gallbladder cancer (GBC) accounts for 1.2% of all global cancer diagnoses, but 1.7% of all cancer deaths. Only 1 in 5 GBC cases in the United States is diagnosed at an early stage, and median survival for advanced stage cancer is no more than about a year. The incidence of the disease is increasing in the developed world. Gallstones, biliary cysts, carcinogen exposure, typhoid, and Helicobacter pylori infection, and abnormal pancreaticobiliary duct junctions are all risk factors, many of which account for its geographical, ethnic and sex distribution. Genetics also plays a strong role, as about a quarter of GBC cases are considered familial, and certain ethnicities, such as Native Americans, are at far higher risk for the neoplasm. Prevention includes weight loss, vaccination against and treatment of bacterial infections, early detection and elimination of polyps and cysts, and avoidance of oral estrogen replacement therapy.
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23
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Sábato C, Bastos-Rodrigues L, Moraes DC, Friedman E, De Marco L, Resende V. Genetic Analysis of Brazilian Patients with Gallbladder Cancer. Pathol Oncol Res 2019; 25:811-814. [PMID: 29552713 DOI: 10.1007/s12253-018-0407-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Accepted: 03/07/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Cristina Sábato
- Department of Surgery, Universidade Federal de Minas Gerais, Av. Alfredo Balena 190, room 114, Belo Horizonte, 30130-100, Brazil
| | | | - Debora Chaves Moraes
- Department of Surgery, Universidade Federal de Minas Gerais, Av. Alfredo Balena 190, room 114, Belo Horizonte, 30130-100, Brazil
| | - Eitan Friedman
- The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, Israel
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Luiz De Marco
- Department of Surgery, Universidade Federal de Minas Gerais, Av. Alfredo Balena 190, room 114, Belo Horizonte, 30130-100, Brazil.
| | - Vivian Resende
- Department of Surgery, Universidade Federal de Minas Gerais, Av. Alfredo Balena 190, room 114, Belo Horizonte, 30130-100, Brazil
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Nemunaitis JM, Brown-Glabeman U, Soares H, Belmonte J, Liem B, Nir I, Phuoc V, Gullapalli RR. Gallbladder cancer: review of a rare orphan gastrointestinal cancer with a focus on populations of New Mexico. BMC Cancer 2018; 18:665. [PMID: 29914418 PMCID: PMC6006713 DOI: 10.1186/s12885-018-4575-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 06/01/2018] [Indexed: 12/18/2022] Open
Abstract
Gallbladder cancer is a rare malignancy of the biliary tract with a poor prognosis, frequently presenting at an advanced stage. While rare in the United States overall, gallbladder cancer has an elevated incidence in geographically distinct locations of the globe including Chile, North India, Korea, Japan and the state of New Mexico in the United States. People with Native American ancestry have a much elevated incidence of gallbladder cancer compared to Hispanic and non-Hispanic white populations of New Mexico. Gallbladder cancer is also one of the few bi-gendered cancers with an elevated female incidence compared to men. Similar to other gastrointestinal cancers, gallbladder cancer etiology is likely multi-factorial involving a combination of genomic, immunological, and environmental factors. Understanding the interplay of these unique epidemiological factors is crucial in improving the prevention, early detection, and treatment of this lethal disease. Previous studies have failed to identify a distinct genomic mutational profile in gallbladder cancers, however, work to identify promising clinically actionable targets is this form of cancer is ongoing. Examples include, interest in the HER2/Neu signaling pathway and the recognition that chronic inflammation plays a crucial role in gallbladder cancer pathogenesis. In this review, we provide a comprehensive overview of gallbladder cancer epidemiology, risk factors, pathogenesis, and treatment with a specific focus on the rural and Native American populations of New Mexico. We conclude this review by discussing future research directions with the goal of improving clinical outcomes for patients of this lethal malignancy.
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Affiliation(s)
- Jacklyn M Nemunaitis
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.,Department of Internal Medicine, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Ursa Brown-Glabeman
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.,Department of Internal Medicine, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Heloisa Soares
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.,Department of Internal Medicine, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Jessica Belmonte
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.,Department of Internal Medicine, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Ben Liem
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.,Department of Internal Medicine, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Itzhak Nir
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.,Department of Surgery, Division of Surgical Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Victor Phuoc
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA.,Department of Surgery, Division of Surgical Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Rama R Gullapalli
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM, USA. .,Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA. .,Department of Chemical and Biological Engineering, University of New Mexico, Room 333A, MSC08-4640, Albuquerque, NM, 87131, USA.
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Sharma A, Sharma KL, Gupta A, Yadav A, Kumar A. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World J Gastroenterol 2017; 23:3978-3998. [PMID: 28652652 PMCID: PMC5473118 DOI: 10.3748/wjg.v23.i22.3978] [Citation(s) in RCA: 259] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 02/01/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developing countries. Late diagnosis and deprived prognosis are major problems for treatment of gallbladder carcinoma. The dramatic associations of this orphan cancer with various genetic and environmental factors are responsible for its poorly defined pathogenesis. An understanding to the relationship between epidemiology, molecular genetics and pathogenesis of gallbladder cancer can add new insights to its undetermined pathophysiology. Present review article provides a recent update regarding epidemiology, pathogenesis, and molecular genetics of gallbladder cancer. We systematically reviewed published literature on gallbladder cancer from online search engine PubMed (http://www.ncbi.nlm.nih.gov/pubmed). Various keywords used for retrieval of articles were Gallbladder, cancer Epidemiology, molecular genetics and bullion operators like AND, OR, NOT. Cross references were manually searched from various online search engines (http://www.ncbi.nlm.nih.gov/pubmed,https://scholar.google.co.in/, http://www.medline.com/home.jsp). Most of the articles published from 1982 to 2015 in peer reviewed journals have been included in this review.
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Ma MZ, Zhang Y, Weng MZ, Wang SH, Hu Y, Hou ZY, Qin YY, Gong W, Zhang YJ, Kong X, Wang JD, Quan ZW. Long Noncoding RNA GCASPC, a Target of miR-17-3p, Negatively Regulates Pyruvate Carboxylase-Dependent Cell Proliferation in Gallbladder Cancer. Cancer Res 2016; 76:5361-5371. [PMID: 27450454 DOI: 10.1158/0008-5472.can-15-3047] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Accepted: 06/15/2016] [Indexed: 02/05/2023]
Abstract
Long noncoding RNAs (lncRNA) are being implicated in the development of many cancers. Here, we report the discovery of a critical role for the lncRNA GCASPC in determining the progression of gallbladder cancer. Differentially expressed lncRNAs and mRNAs between gallbladder cancer specimens and paired adjacent nontumor tissues from five patients were identified and validated by an expression microarray analysis. Quantitative real-time PCR was used to measure GCASPC levels in tissues from 42 gallbladder cancer patients, and levels of GCASPC were confirmed further in a separate cohort of 89 gallbladder cancer patients. GCASPC was overexpressed or silenced in several gallbladder cancer cell lines where molecular and biological analyses were performed. GCASPC levels were significantly lower in gallbladder cancer than adjacent nontumor tissues and were associated with tumor size, American Joint Committee on Cancer tumor stage, and patient outcomes. GCASPC overexpression suppressed cell proliferation in vitro and in vivo, whereas GCASPC silencing had opposite effects. By RNA pull-down and mass spectrometry, we identified pyruvate carboxylase as an RNA-binding protein that associated with GCASPC. Because GCASPC is a target of miR-17-3p, we confirmed that both miR-17-3p and GCASPC downregulated pyruvate carboxylase level and activity by limiting protein stability. Taken together, our results defined a novel mechanism of lncRNA-regulated cell proliferation in gallbladder cancer, illuminating a new basis for understanding its pathogenicity. Cancer Res; 76(18); 5361-71. ©2016 AACR.
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Affiliation(s)
- Ming-Zhe Ma
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Gastric Cancer and Soft Tissue Sarcoma, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yan Zhang
- Department of Gastroenterology, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Ming-Zhe Weng
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shou-Hua Wang
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ye Hu
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhao-Yuan Hou
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi-Yu Qin
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Gong
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yong-Jie Zhang
- Second Department of Biliary Surgery and Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xiang Kong
- Department of Endocrinology, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China.
| | - Jian-Dong Wang
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Zhi-Wei Quan
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Abstract
In this review, the authors present an updated description of gallbladder cancer in 2 sections based on presentation: disease that presents incidentally following laparoscopic cholecystectomy and malignancy that is suspected preoperatively. Elements pertaining to technical aspects of surgical resection provide the critical focus of this review and are discussed in the context of evidence-based literature on gallbladder cancer today.
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Affiliation(s)
- Motaz Qadan
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - T Peter Kingham
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Does the Frequency of Cholecystectomy Affect the Ensuing Incidence of Gallbladder Cancer in Sweden? A Population-Based Study with a 16-Year Coverage. World J Surg 2016; 40:66-72. [PMID: 26470697 DOI: 10.1007/s00268-015-3267-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Gallbladder cancer (GBC) is rare among the different gastrointestinal cancers with a significant global variation in incidence. High cholecystectomy rates on benign indications have been assumed to prevent the development of gallbladder cancer. The aim of the present study was to explore the relationship between the rate of cholecystectomy at different time periods and regions of the country and the annual incidence of GBC. METHODS Standardized cholecystectomy and GBC incidences for Swedish counties have been obtained from the Swedish national inpatient and National Cancer registries for the years 1998–2013. The incidences have been calculated for ages over 15 years and per 100,000 population. The relationships between cholecystectomy and GBC incidences have been analyzed using regression models. Correlation analyses were performed for the total cumulative incidence rates as well as the incidence rates calculated for the first and last 8 years of the entire study period. RESULTS Cholecystectomy rates ranged from 99 to 205 per 100,000 and year, and the GBC incidence from 2.3 to 5.1. Overall, we observed a slow but steady decline in cholecystectomy rates—as well as GBC incidences during the 16-year period. No significant correlation between the cholecystectomy rates and GBC incidences was seen. CONCLUSIONS This nationwide population-based study demonstrates substantial geographic differences in annual cholecystectomy rates without any significant inverse co-variation between cholecystectomy rates and the ensuing GBC incidence which would have supported the idea that frequent cholecystectomy affects the incidence of GBC.
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EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones. J Hepatol 2016; 65:146-181. [PMID: 27085810 DOI: 10.1016/j.jhep.2016.03.005] [Citation(s) in RCA: 333] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 03/09/2016] [Indexed: 02/06/2023]
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Cholesterol Gallstones Larger Than 3 cm Appear to Be Associated With Gallbladder Cancer: Identification of a High Risk Group of Patients That Could Benefit From Preventive Cholecystectomy. Ann Surg 2016; 263:e56. [PMID: 25793627 DOI: 10.1097/sla.0000000000001082] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Espinoza JA, Bizama C, García P, Ferreccio C, Javle M, Miquel JF, Koshiol J, Roa JC. The inflammatory inception of gallbladder cancer. Biochim Biophys Acta Rev Cancer 2016; 1865:245-54. [PMID: 26980625 DOI: 10.1016/j.bbcan.2016.03.004] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 03/09/2016] [Accepted: 03/10/2016] [Indexed: 02/06/2023]
Abstract
Gallbladder cancer is a lethal disease with notable geographical variations worldwide and a predilection towards women. Its main risk factor is prolonged exposure to gallstones, although bacterial infections and other inflammatory conditions are also associated. The recurrent cycles of gallbladder epithelium damage and repair enable a chronic inflammatory environment that promotes progressive morphological impairment through a metaplasia-dysplasia-carcinoma, along with cumulative genome instability. Inactivation of TP53, which is mutated in over 50% of GBC cases, seems to be the earliest and one of the most important carcinogenic pathways involved. Increased cell turnover and oxidative stress promote early alteration of TP53, cell cycle deregulation, apoptosis and replicative senescence. In this review, we will discuss evidence for the role of inflammation in gallbladder carcinogenesis obtained through epidemiological studies, genome-wide association studies, experimental carcinogenesis, morphogenetic studies and comparative studies with other inflammation-driven malignancies. The evidence strongly supports chronic, unresolved inflammation as the main carcinogenic mechanism of gallbladder cancer, regardless of the initial etiologic trigger. Given this central role of inflammation, evaluation of the potential for GBC prevention removing causes of inflammation or using anti-inflammatory drugs in high-risk populations may be warranted.
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Affiliation(s)
- Jaime A Espinoza
- SciLifeLab, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Stockholm SE171 76, Sweden
| | - Carolina Bizama
- Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), UC-Center for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Patricia García
- Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), UC-Center for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Catterina Ferreccio
- Department of Public Health, Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Milind Javle
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Juan F Miquel
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Jill Koshiol
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda 20850, MD, USA
| | - Juan C Roa
- Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), UC-Center for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
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Jiao X, Wu Y, Zhou L, He J, Yang C, Zhang P, Hu R, Luo C, Du J, Fu J, Shi J, He R, Li D, Jun W. Variants and haplotypes in Flap endonuclease 1 and risk of gallbladder cancer and gallstones: a population-based study in China. Sci Rep 2015; 5:18160. [PMID: 26668074 PMCID: PMC4678911 DOI: 10.1038/srep18160] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 11/13/2015] [Indexed: 12/16/2022] Open
Abstract
The role of FEN1 genetic variants on gallstone and gallbladder cancer susceptibility is unknown. FEN1 SNPs were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method in blood samples from 341 gallbladder cancer patients and 339 healthy controls. The distribution of FEN1-69G > A genotypes among controls (AA, 20.6%; GA, 47.2% and GG 32.2%) was significantly different from that among gallbladder cancer cases (AA, 11.1%; GA, 48.1% and GG, 40.8%), significantly increased association with gallbladder cancer was observed for subjects with both the FEN1-69G > A GA (OR = 1.73, 95% CI = 1.01-2.63) and the FEN1-69G > A GG (OR = 2.29, 95% CI = 1.31-3.9). The distribution of FEN1 -4150T genotypes among controls (TT, 21.8%;GT, 49.3% and GG 28.9%) was significantly different from that among gallbladder cancer cases (TT, 12.9%; GT, 48.4% and GG 38.7%), significantly increased association with gallbladder cancer was observed for subjects with both the FEN1-4150T GT(OR = 1.93, 95% CI = 1.04-2.91) and the FEN1-4150T GG(OR = 2.56, 95% CI = 1.37-5.39). A significant trend towards increased association with gallbladder cancer was observed with potentially higher-risk FEN1-69G > A genotypes (P < 0.001, χ2 trend test) and FEN14150G > T (P < 0.001, χ2 trend test) in gallstone presence but not in gallstone absence (P = 0.81, P = 0.89, respectively). In conclusion, this study revealed firstly that FEN1 polymorphisms and haplotypes are associated with gallbladder cancer risk.
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Affiliation(s)
- Xingyuan Jiao
- Department of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
- Department of General Surgery and Transplantation Surgery, University Hospital Duisburg-Essen, D-45122, Germany
| | - Ying Wu
- Department of Biostatistics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Liansuo Zhou
- Department of General Surgery, The First Affiliated Hospital, Xian Medical College, Xian 710061, China
| | - Jinyun He
- Department of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Chonghua Yang
- Department of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Peng Zhang
- Department of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Ronglin Hu
- Department of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Canqiao Luo
- Deparment of Pathology, Sun Yat-Sen University School of Medicine, Guangzhou 510080, China
| | - Jun Du
- Department of Molecular Biology, Sun Yat-Sen University School of Pharmacy, Guangzhou 510080, China
| | - Jian Fu
- Department of General Surgery and Transplantation Surgery, University Hospital Duisburg-Essen, D-45122, Germany
| | - Jinsen Shi
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xian Jiaotong University, Xian 710061, China
| | - Rui He
- Department of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Dongming Li
- Department of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Wang Jun
- Department of Anatomy, Shenzhen University School of Medicine, Shenzhen 518060, China
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Abstract
OPINION STATEMENT A paradigm shift towards molecular-based, personalized cancer therapeutics has occurred in recent years and a number of targeted drugs have emerged. Various targeted therapies like erlotinib, trastuzumab, and cetuximab have been approved in lung, breast, and colon cancers, respectively. Numerous clinical trials involving targeted drugs in biliary tract cancers are currently in progress, though none have been approved for this disease. Biliary tract cancers are divided into separate entities both anatomically and in terms of pathogenesis but are grouped together in most trials given their rarity. Combination chemotherapy involving cisplatin and gemcitabine is the current standard of care in the metastatic setting. In this review, we will discuss the various molecular pathways implicated in biliary tract cancers and potential therapeutic targets.
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Affiliation(s)
- Amartej Merla
- Department of Medical Oncology, Montefiore Medical Center, 1695 Eastchester Road, 2nd Floor, Bronx, NY 10461 USA
| | - Kenneth G. Liu
- Department of Medical Oncology, Montefiore Medical Center, 1695 Eastchester Road, 2nd Floor, Bronx, NY 10461 USA
| | - Lakshmi Rajdev
- Department of Medical Oncology, Montefiore Medical Center, 1695 Eastchester Road, 2nd Floor, Bronx, NY 10461 USA
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Abstract
PURPOSE OF REVIEW Gallbladder cancer (GBC) should be considered an orphan disease in oncology and represent a unique carcinogenetic model. This review will analyse some of the current aspects of GBC. RECENT FINDINGS Chile has the highest incidence and mortality of GBC in the world. Most patients are diagnosed in advanced stages with few treatment options. During the last two decades, little progress has been made in early diagnosis and treatment. At the molecular level, recent access to next-generation sequencing and other techniques for detecting the mutations of multiple genes have made advances in this area. SUMMARY The use of therapies targeted according to the detection of specific molecular alterations is in the early stages of evaluation and could represent a significant advance in the treatment of a large number of patients from developing countries.
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Shang YS, Zou ZP, Huang JG. Relationship between gallstones and local invasion of gallbladder carcinoma. Shijie Huaren Xiaohua Zazhi 2015; 23:990-993. [DOI: 10.11569/wcjd.v23.i6.990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the relationship between the local invasion of gallbladder carcinoma and the features of gallstones, such as quantity and diameter.
METHODS: One hundred fifty patients with pathologically confirmed gallbladder carcinoma were analyzed. The relationship between gallstones and the Nevin stage of gallbladder carcinoma was analyzed.
RESULTS: Stages Ⅳ and Ⅴ gallbladder carcinoma was more commonly seen in patients with gallbladder stones (χ2 = 6.15, P < 0.05), especially those with stones greater than 2 cm in diameter (χ2 = 5.79, P < 0.05). However, the number of stones (single or multiple) showed no significant correlation with the Nevin stage of gallbladder carcinoma (χ2 = 0.13, P > 0.05).
CONCLUSION: Gallbladder carcinoma patients with gallbladder stones, especially those greater than 2 cm in diameter, tend to have a more serious disease.
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Bizama C, García P, Espinoza JA, Weber H, Leal P, Nervi B, Roa JC. Targeting specific molecular pathways holds promise for advanced gallbladder cancer therapy. Cancer Treat Rev 2015; 41:222-34. [PMID: 25639632 DOI: 10.1016/j.ctrv.2015.01.003] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Revised: 01/12/2015] [Accepted: 01/13/2015] [Indexed: 02/07/2023]
Abstract
Gallbladder cancer is the most common and aggressive malignancy of the biliary tract. The complete surgical resection is the only potentially curative approach in early stage; however, most cases are diagnosed in advanced stages and the response to traditional chemotherapy and radiotherapy is extremely limited, with modest impact in overall survival. The recent progress in understanding the molecular alterations of gallbladder cancer has shown great promise for the development of more effective treatment strategies. This has mainly resulted from the identification of molecular alterations in relevant intracellular signaling pathways-Hedgehog, PI3K/AKT/mTOR, Notch, ErbB, MAPK and angiogenesis-which are potential tailored targets for gallbladder cancer patients. This review discusses the recent remarkable progress in understanding the molecular alterations that represent novel prognosis molecular markers and therapeutic targets for gallbladder cancer, which will provide opportunities for research and for developing innovative strategies that may enhance the benefit of conventional chemotherapy, or eventually modify the fatal natural history of this orphan disease.
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Affiliation(s)
- Carolina Bizama
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Patricia García
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Jaime A Espinoza
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Helga Weber
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco 4811230, Chile
| | - Pamela Leal
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco 4811230, Chile
| | - Bruno Nervi
- Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 26767000, Chile
| | - Juan Carlos Roa
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
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